Fragile x mental retardation protein (fmrp), compositions, and methods related thereto

Abstract

The invention relates to fragile X mental retardation protein (FMKP), compositions, and methods related thereto. In certain embodiments, the invention relates to treating a neurological disorder by administering a P 13 K antagonist to a subject in need thereof. In other embodiments, the invention relates to methods of diagnosing neurological disorders.

1 . A method of treating or preventing a disease related to fragile X mental retardation protein (FMRP) comprising administering a PI3K antagonist to a subject at risk of, exhibiting symptoms of , or diagnosed with the disease. 
     
     
         2 . A method of treating synapse defects in the brain comprising administering a PI3K antagonist to a subject. 
     
     
         3 . The method of  claim 1 , wherein the subject is diagnosed with fragile X syndrome, autism, or an autism spectrum disorder. 
     
     
         4 . The method of  claim 1 , wherein the PI3K antagonist is a broad spectrum PI3K antagonist. 
     
     
         5 . The method of  claim 1 , wherein the PI3K antagonist preferentially binds p110beta. 
     
     
         6 . The method of  claim 1 , wherein the PI3K antagonist is siNA of PI3K. 
     
     
         7 . The method of  claim 1 , wherein the PI3K antagonist is siRNA of p110beta. 
     
     
         8 . The method of  claim 1 , wherein the PI3K antagonist is an antibody to PI3K. 
     
     
         9 . The method of  claim 1 , wherein the PI3K antagonist is an antibody to p110beta. 
     
     
         10 . The method of  claim 1 , wherein the PI3K antagonist is an aptamer to PI3K. 
     
     
         11 . The method of  claim 1 , wherein the PI3K antagonist is an aptamer to p110beta. 
     
     
         12 . The method of  claim 1 , wherein the PI3K antagonist is wortmannin, 2-morpholin-4-yl-8-phenylchromen-4-one, 4-(2-(1H-indazol-4-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine, N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide, (R)-2-(1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethylamino)benzoic acid, acetic acid (1S,4E,10R,11R,13S,14R)-[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7,17-trioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[α]phenanthren-11-yl ester, N-(3-(benzo[c][1,2,5]thiadiazol-5-ylamino)quinoxalin-2-yl)-4-methylbenzenesulfonamide, 24(6-amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one, 2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)propanenitrile, 7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1, 2-a]pyrimidin-4-one, 3-[4-(4-morpholinyl)pyrido[3′,′:4,5]furo[3,2-d]pyrimidin-2-yl]-phenol, 5-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-ylmethylene]-thiazolidine-2,4-dione, 5-(6-quinoxalinylmethylene)-2,4-thiazolidinedione, 5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylene]-2,4-thiazolidinedione, (Z)-5-((4-(pyridin-4-yl)quinolin-6-yl)methylene)thiazolidine-2,4-dione, 3,3′-(2,4-diaminopteridine-6,7-diyl)diphenol or salt or prodrug thereof. 
     
     
         13 . The method of  claim 12  wherein the prodrug is RGDS-conjugated prodrug of morpholin-4-yl-8-phenylchromen-4-one. 
     
     
         14 . A method of diagnosing a disease related to fragile X mental retardation protein (FMRP) comprising assaying a sample from a subject for excessive PI3K or PI3K activity and correlating excessive PI3K or PI3K activity to a disease related to FMRP. 
     
     
         15 . The method of  claim 14 , wherein the disease is fragile X, autism, or an autism spectrum disorder. 
     
     
         16 . The method of  claim 14 , wherein assaying comprises detecting PI3K, p85 or p110 subunits and comparing the detected amount to that typically found in a sample from a person with or without a disease related to fragile X mental retardation protein. 
     
     
         17 . The method of  claim 16 , wherein PI3K, p85 or p110 subunits are detected by mass spectroscopy. 
     
     
         18 . The method of  claim 15 , wherein assaying comprising detecting phosphatidylinositol 3-phosphate in the sample and comparing the detected amount to that typically found in a sample from a person with or without a disease related to fragile X mental retardation protein. 
     
     
         19 . The method of  claim 14 , wherein the phosphatidylinositol 3-phosphate is detected by mass spectroscopy. 
     
     
         20 . The method of  claim 14 , wherein the assaying comprises isolating PI3K, p85 or p110 subunits from the sample providing isolates and measuring PI3K activity in the isolates. 
     
     
         21 . The method of  claim 14 , wherein the assaying comprises, combining the sample and affinity markers for PI3K, p85 or p110 subunits and measuring markers in the marker bound sample. 
     
     
         22 . The method of  claim 21 , wherein the markers are antibodies for PI3K, p85, or p110 subunit. 
     
     
         23 . The method of  claim 22 , wherein the markers are fluorescent. 
     
     
         24 . The method of  claim 14 , wherein the assaying comprises the step of detecting expression of mRNA encoding PI3K, p85, or p110 subunit in the sample. 
     
     
         25 . The method of  claim 14 , wherein the assaying comprises, mixing the sample with a polynucleotide that hybridizes to mRNA encoding PI3K, p85, or p110 subunit. 
     
     
         26 . The method of  claim 25 , wherein the polynucleotide is conjugated to a fluorescent marker. 
     
     
         27 . The method of claim  29 , wherein assaying comprises moving the sample through separation medium and detecting PI3K, p85, or p110 subunit, phosphatidylinositol 3-phosphate, mRNA encoding PI3K, p85, or p110, or PI3K activity. 
     
     
         28 . The method of  claim 14 , wherein the sample comprises a lymphocyte or fibroblast.